Disorders of sexual differentiation Flashcards
Define Gonadal dysgenesis
- Sexual differentiation is incomplete. Usually missing SRY in male, or partial or complete deletion of second X in female. Also used as a general description of abnormal development of the gonads.
Define Sex reversal
- Phenotype does not match genotype, ie may be male genotypically but externally look like a female.
Define intersex
- Have some components of both tracts or have ambiguous genitalia. Sex of an infant difficult to determine.
What are the characteristics of androgen sensitivity syndrome (AIS) ?
what are the effects in males?
- Testosterone is made but it has no effect
Testes form and make AMH so Mullerian ducts regress.
-No differentiation of Wolffian ducts
( testosterone has no effect)
-No external male genitalia
(testosterone is converted to DHT but have no effect)
What are the characteristics of complete AIS?
Undescended testes.
No uterus or fallopian tubes
External genitalia appear female - abbreviated blind vaginal pouch.
Usually present with primary amenorrhoea. Lack of body hair is a clue.
Ultrasound scan and karyotype with male levels of androgens.
Hormonal puberty may be feminizing without intervention due to aromatization of endogenous androgens to estrogens. Lacking response to androgen.
Sex assignment and rearing almost always female.
Differentiation of gender role and identity usually feminine. In adulthood, sexuality often conforms to typical heterosexual female expectations.
What are the characteristics of partial AIS?
Spectrum of phenotypes including almost normal female external genitalia through ambiguous genitalia (perineoscrotal hypospadias, microphallus, cryptorchidism).
Minor genital deviations go unnoticed or may be surgically repaired.
At puberty development of male secondary characteristics may not be very pronounced.
In some cases pubertal gynecomastia (androgen/estrogen ratio) or ambiguous genitalia surgically corrected. Androgen therapy in some cases.
Majority of individuals develop an identity commensurate with their assigned gender - around 20% desire to change gender usually in adolescence or adulthood
What is Persistent Mullerian duct syndrome?
(PMDS)
an XY male is unable to make or respond to AMH in utero.
Testes form and either fail to make AMH or AMH receptors absent.
Mullerian ducts remain.
Differentiation of Wolffian ducts and masculinised external genitalia
What are the types of PMDS?
PMDS type I results from mutations of the gene for AMH on chromosome 19.
PMDS type II results from mutations of the gene for the AMH receptor (AMH-RII) on chromosome 12.
Both autosomal recessive conditions with expression usually limited to XY offspring
Describe the presentation of PMDS
60–70% of cases have intra-abdominal Mullerian structures and testes in a position simulating that of the ovaries
20–30% have one testis in a hernial sac or scrotum together with Mullerian structures.
10% have both testes located in the same hernial sac (transverse testicular ectopia) along with the uterine tubes and/or uterine structures.
All have an increased risk of malignant transformation.
What is the treatment of PMDS
Surgery (orchiopexy) to retrieve the testes and position them in the scrotum. If testes cannot be retrieved, testosterone replacement at puberty is an option.
Removal of uterus dissection of Müllerian tissue away from the vas deferens/epididymis.
Laparoscopic hysterectomy may prevent the occurrences of neoplastic tissue formation.
What are the characteristics of 5-alpha reductase deficiency?
How does it present?
Testosterone is made but not DHT
Testes form, AMH acts, testosterone acts. Internal structures form. External male structures do not fully develop.
May appear mainly female or may have ambiguous genitalia such as labioscrotal folds or clitoridean penis. The degree of the enzyme block varies and so therefore does the presentation.
Need to assess potential as high testosterone level which will occur at adrenarche and puberty may induce virilisation.
Both testosterone and dihydrotestosterone (DHT) are capable of masculinising the brain in non-human primates so some brain masculinisation in utero possible with this condition.
What are the characteristics of Turners syndrome ?
How does it present?
What is the treatment
Women have a missing X chromsome
XO have failure of ovarian function. ‘Streak’ ovaries = ovarian dysgenesis - illustrates that we need two X’s for ovarian development.
Uterus and tubes are present, may be small or other defects in growth and development. Wide spectrum of phenotypic disorders and severity.
May be fertile, many have mosaicism. Female gender.
Hormone support of bones and uterus.
What are the characteristics of congenital adrenal hyperplasia (CAH) ?
An XX female exposed to high levels of androgens in utero
Block in the enzyme 21-Hydroxylase results in the failure to synthesise cortisol, this affects the Hypothalamic Pituitary Adrenal Axis.
hypothalumus: CRH (+ feedback)
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Pituitary: ACTH Stimulates rapid uptake of cholesterol into the adrenal cortex.
Upregulates cholesterol side-chain cleavage enzyme (P450scc). Increases glucocorticoid secretion(+ feedback)
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Adrenal gland: cortisol (- feedback)
Increased CRH and ACTH stimulate cholesterol uptake and adrenal cortex activity. Cortisol itself doesn’t rise because of enzyme block
More progestagens build up and so they get converted to androgens
No SRY so no testes and no AMH.
Mullerian ducts remain.
Masculinised external genitalia, but androgen levels not usually high enough to rescue Wolffian ducts.
please review slides 18-23 for images
What is the presentation of CAH?
The completeness of the enzyme block varies. May have developed Wolffian structures and ambiguous masculinised external genitalia or hirsutism.
Early studies suggested that XX patients assigned as girls developed female gender identity, but with more masculine childhood behaviour and lower maternal interest as adults.
Also in CAH need to be aware of the possibility of ‘salt-wasting’ due to a lack of aldosterone, this can be lethal.
Treatment with glucocorticoids to correct feedback.
summary
Correct sexual differentiation requires genetic, anatomical and endocrine components.
Disorders are rare, but have allowed scientists to understand the requirements for normal development.
Diagnosis and treatment of conditions of abnormal sexual differentiation requires a specialist team.
Long-term functioning of the person now the primary issue rather than immediate ‘corrective’ surgery.
